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1.
RSC advances ; 11(48):30132-30147, 2021.
Article in English | EuropePMC | ID: covidwho-1812811

ABSTRACT

Continuing reports of new SARS-CoV-2 variants have caused worldwide concern and created a challenging situation for clinicians. The recently reported variant B.1.618, which possesses the E484K mutation specific to the receptor-binding domain (RBD), as well as two deletions of Tyr145 and His146 at the N-terminal binding domain (NTD) of the spike protein, must be studied in depth to devise new therapeutic options. Structural variants reported in the RBD and NTD may play essential roles in the increased pathogenicity of this SARS-CoV-2 new variant. We explored the binding differences and structural-dynamic features of the B.1.618 variant using structural and biomolecular simulation approaches. Our results revealed that the E484K mutation in the RBD slightly altered the binding affinity through affecting the hydrogen bonding network. We also observed that the flexibility of three important loops in the RBD required for binding was increased, which may improve the conformational optimization and consequently binding of the new variant. Furthermore, we found that deletions of Tyr145 and His146 at the NTD reduced the binding affinity of the monoclonal antibody (mAb) 4A8, and that the hydrogen bonding network was significantly affected consequently. This data show that the new B.1.618 variant is an antibody-escaping variant with slightly altered ACE2–RBD affinity. Moreover, we provide insights into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD. Our results suggest the need for further in vitro and in vivo studies that will facilitate the development of possible therapies for new variants such as B.1.618. This study explored the binding patterns of the wild type and B.1.618 variant using which revealed that the B.1.618 variant possess a stronger binding affinity for the host ACE2 and escape the neutralizing antibodies.

2.
Diabetes Metab Res Rev ; : e3526, 2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1729121

ABSTRACT

OBJECTIVE: To build a clinical risk score to aid risk stratification among hospitalised COVID-19 patients. METHODS: The score was built using data of 417 consecutive COVID-19 in patients from Kuwait. Risk factors for COVID-19 mortality were identified by multivariate logistic regressions and assigned weighted points proportional to their beta coefficient values. A final score was obtained for each patient and tested against death to calculate an Receiver-operating characteristic curve. Youden's index was used to determine the cut-off value for death prediction risk. The score was internally validated using another COVID-19 Kuwaiti-patient cohort of 923 patients. External validation was carried out using 178 patients from the Italian CoViDiab cohort. RESULTS: Deceased COVID-19 patients more likely showed glucose levels of 7.0-11.1 mmol/L (34.4%, p < 0.0001) or >11.1 mmol/L (44.3%, p < 0.0001), and comorbidities such as diabetes and hypertension compared to those who survived (39.3% vs. 20.4% [p = 0.0027] and 45.9% vs. 26.6% [p = 0.0036], respectively). The risk factors for in-hospital mortality in the final model were gender, nationality, asthma, and glucose categories (<5.0, 5.5-6.9, 7.0-11.1, or 11.1 > mmol/L). A score of ≥5.5 points predicted death with 75% sensitivity and 86.3% specificity (area under the curve (AUC) 0.901). Internal validation resulted in an AUC of 0.826, and external validation showed an AUC of 0.687. CONCLUSION: This clinical risk score was built with easy-to-collect data and had good probability of predicting in-hospital death among COVID-19 patients.

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329300

ABSTRACT

Introduction: SARS-CoV-2 vaccination has been effective in protecting against severe COVID-19 infections and related mortality. It is recommended for all individuals including patients with inflammatory bowel disease (IBD). However, safety data is lacking in this group of patients. Therefore, we aim to evaluate the short- and long-term vaccine related adverse events (AEs) in patients with IBD. Methods: This is a prospective, observational cohort study investigating short- and long-term AEs related to BNT162b2 vaccine in patients with IBD (study group) after first and second dose compared to healthy participants (study group). Patients were recruited at the time of attendance to clinic or infusion rooms. Short term (<3 weeks) localized and systemic AEs were assessed via questionnaire. Follow-up phone-based survey was made to collect data on long term (up to 24 weeks) AEs. Results A total of 408 patients answered the questionnaires, 204 patients in each group, the study and control group. No serious adverse events were reported in either the study nor the control group after the first or the second dose. Participants in the control group reported more frequent pain at the injection site than those in the study group after the first dose (58 (57%) vs 38 (37%) respectively, P-value= 0.005). After the second dose, tiredness was reported more frequently in the control group [49 (48%)] compared to the study group [25 (24%), (P-value<0.001)]. At 20-24 weeks post vaccination, 386 out of 408 (94.6%) patients were willing to participate in the follow-up phone based questionnaire (196 (96.1%) in the study group vs 190 (93.1%) in the control group). In both groups, none of the patients reported local, systemic or severe adverse events (0 out of 386) at week 20-244 post second dose. Conclusion: The BNT162b2 vaccine is safe in patients with IBD. No severe or long-term adverse events were reported in our study. The frequency of local and systemic adverse events after the second dose was generally higher among healthy participants compared to patients with IBD. Further studies including a larger cohort with longer follow-up duration are needed to assess for possible rare adverse events.

4.
Front Public Health ; 9: 778243, 2021.
Article in English | MEDLINE | ID: covidwho-1581109

ABSTRACT

Background: The emergence of new COVID-19 variants of concern coupled with a global inequity in vaccine access and distribution has prompted many public health authorities to circumvent the vaccine shortages by altering vaccination protocols and prioritizing persons at high risk. Individuals with previous COVID-19 infection may not have been prioritized due to existing humoral immunity. Objective: We aimed to study the association between previous COVID-19 infection and antibody levels after COVID-19 vaccination. Methods: A serological analysis to measure SARS-CoV-2 immunoglobulin (Ig)G, IgA, and neutralizing antibodies was performed on individuals who received one or two doses of either BNT162b2 or ChAdOx1 vaccines in Kuwait. A Student t-test was performed and followed by generalized linear regression models adjusted for individual characteristics and comorbidities were fitted to compare the average levels of IgG and neutralizing antibodies between vaccinated individuals with and without previous COVID-19 infection. Results: A total of 1,025 individuals were recruited. The mean levels of IgG, IgA, and neutralizing antibodies were higher in vaccinated subjects with previous COVID-19 infections than in those without previous infection. Regression analysis showed a steeper slope of decline for IgG and neutralizing antibodies in vaccinated individuals without previous COVID-19 infection compared to those with previous COVID-19 infection. Conclusion: Previous COVID-19 infection appeared to elicit robust and sustained levels of SARS-CoV-2 antibodies in vaccinated individuals. Given the inconsistent supply of COVID-19 vaccines in many countries due to inequities in global distribution, our results suggest that even greater efforts should be made to vaccinate more people, especially individuals without previous COVID-19 infection.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2 , Vaccination
5.
Vaccines (Basel) ; 9(12)2021 Dec 13.
Article in English | MEDLINE | ID: covidwho-1572689

ABSTRACT

Introduction: The immunogenicity of SARS-CoV-2 vaccines in patients with inflammatory bowel disease (IBD) on biologic therapies is not well studied. The goal of this study was to measure the serological response to BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD receiving different biologic therapies. Methods: We performed a multi-center prospective study between 1 August 2021 and 15 September 2021. We measured the seropositivity of SARS-CoV-2 antibodies (SARS-CoV-2 IgG) and neutralizing antibody concentrations in patients with IBD receiving biologic therapies 4-10 weeks after their second dose or 3-6 weeks after their first dose of BNT162b2 or ChAdOx1 nCoV-19 vaccines. Results: A total of 126 patients were enrolled (mean age, 31 years; 60% male; 71% Crohn's disease, 29% ulcerative colitis). Of these, 92 patients were vaccinated with the BNT162b2 vaccine (73%) and 34 patients with the ChAdOx1 nCoV-19 vaccine (27%). In patients being treated with infliximab and adalimumab, the proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving two doses of the vaccine were 44 out of 59 patients (74.5%) and 13 out of 16 patients (81.2%), respectively. In contrast, of those receiving ustekinumab and vedolizumab, the proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving two doses of the vaccine were 100% and 92.8%, respectively. In patients receiving infliximab and adalimumab, the proportion of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels after two-dose vaccination was 40 out of 59 patients (67.7%) and 14 out 16 patients (87.5%), respectively. On the other hand, the proportion of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels were 12 out of 13 patients (92.3%) and 13 out of 14 patients (92.8%) in patients receiving ustekinumab and vedolizumab, respectively. Conclusions: The majority of patients with IBD who were on infliximab, adalimumab, and vedolizumab seroconverted after two doses of SARS-CoV-2 vaccination. All patients on ustekinumab seroconverted after two doses of SARS-CoV-2 vaccine. The BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines are both likely to be effective after two doses in patients with IBD on biologics. Larger follow-up studies are needed to evaluate if decay of antibodies occurs over time.

6.
Frontiers in immunology ; 12, 2021.
Article in English | EuropePMC | ID: covidwho-1563796

ABSTRACT

The emergence of effective vaccines for COVID-19 has been welcomed by the world with great optimism. Given their increased susceptibility to COVID-19, the question arises whether individuals with type-2 diabetes mellitus (T2DM) and other metabolic conditions can respond effectively to the mRNA-based vaccine. We aimed to evaluate the levels of anti-SARS-CoV-2 IgG and neutralizing antibodies in people with T2DM and/or other metabolic risk factors (hypertension and obesity) compared to those without. This study included 262 people (81 diabetic and 181 non-diabetic persons) that took two doses of BNT162b2 (Pfizer–BioNTech) mRNA vaccine. Both T2DM and non-diabetic individuals had a robust response to vaccination as demonstrated by their high antibody titers. However, both SARS-CoV-2 IgG and neutralizing antibodies titers were lower in people with T2DM. The mean ( ± 1 standard deviation) levels were 154 ± 49.1 vs. 138 ± 59.4 BAU/ml for IgG and 87.1 ± 11.6 vs. 79.7 ± 19.5% for neutralizing antibodies in individuals without diabetes compared to those with T2DM, respectively. In a multiple linear regression adjusted for individual characteristics, comorbidities, previous COVID-19 infection, and duration since second vaccine dose, diabetics had 13.86 BAU/ml (95% CI: 27.08 to 0.64 BAU/ml, p=0.041) less IgG antibodies and 4.42% (95% CI: 8.53 to 0.32%, p=0.036) fewer neutralizing antibodies than non-diabetics. Hypertension and obesity did not show significant changes in antibody titers. Taken together, both type-2 diabetic and non-diabetic individuals elicited strong immune responses to SARS-CoV-2 BNT162b2 mRNA vaccine;nonetheless, lower levels were seen in people with diabetes. Continuous monitoring of the antibody levels might be a good indicator to guide personalized needs for further booster shots to maintain adaptive immunity. Nonetheless, it is important that people get their COVID-19 vaccination especially people with diabetes.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295995

ABSTRACT

Background Vaccination is a promising strategy to protect vulnerable groups like inflammatory bowel disease (IBD) patients against COVID-19 and associated severe outcomes. COVID-19 Vaccines clinical trials excluded IBD patients taking infliximab with azathioprine or 6-mercaptopurine (infliximab combination). Therefore, we sought to evaluate serologic responses to COVID-19 vaccination with the mRNA vaccine, BNT162b2 in IBD patients receiving infliximab combination therapy compared to healthy participants. Methods This is a multicenter prospective study. IBD patients were recruited at the time of attendance at infusion center between August 1 st , 2021, and September 15 th , 2021. Our primary outcome was the concentrations of SARS-CoV-2 antibodies 4-10 weeks after vaccination with two doses of BNT162b2 vaccine in IBD patients taking infliximab combination therapy (study group) compared to healthy participants group (control group). Both study and healthy participants groups were matched for age, sex and time-since-last-vaccine-dose using optimal pair matching method. Results In total 116 participants were recruited in the study, 58 patients in the study group and 58 in the control group. Median (IQR) IgG concentrations were lower in the study group [99 BAU/mL (40, 177)] than the control group [139 BAU/mL (120, 188)], following vaccination (p = 0.0032). Neutralizing antibodies was also lower in the study group compared to the control group [64% (23, 94) vs 91% (85, 94), p <0.001]. The median IgA levels in the study group was also significantly lower when compared to the control group [6 U/ml (3, 34) vs 13 U/ml (7, 30), p =0.0097]. In the study group, the percentage of patients who achieved positive IgG, neutralizing antibody and IgA levels were 81%, 75% and 40% respectively. In the control group, all participants (100%) had positive IgG and neutralizing antibody levels while 62% had positive IgA levels. Conclusion In patients with IBD receiving infliximab combination therapy, IgG, IgA and neutralizing antibody levels after BNT162b2 vaccine were lower compared to healthy participants. However, most patients treated with infliximab combination therapy seroconverted after two doses of the vaccine.

8.
J Clin Med ; 10(22)2021 Nov 18.
Article in English | MEDLINE | ID: covidwho-1524042

ABSTRACT

BACKGROUND: Vaccination is a promising strategy to protect vulnerable groups like inflammatory bowel disease (IBD) patients against COVID-19 and associated severe outcomes. COVID-19 vaccine clinical trials excluded IBD patients taking infliximab with azathioprine or 6-mercaptopurine (infliximab combination). Therefore, we sought to evaluate serologic responses to COVID-19 vaccination with the mRNA vaccine, BNT162b2, in patients with IBD receiving infliximab combination therapy compared with healthy participants. METHOD: This was a multicenter prospective study. Patients with IBD were recruited at the time of attendance at infusion center between 1 August 2021, and 15 September 2021. Our primary outcome were the concentrations of SARS-CoV-2 antibodies 4-10 weeks after vaccination with two doses of BNT162b2 vaccine in patients with IBD taking infliximab combination therapy (study group) compared with a healthy participants group (control group). Both study and control groups were matched for age, sex, and time-since-last-vaccine-dose using optimal pair-matching method. RESULTS: In total, 116 participants were recruited in the study, 58 patients in the study group and 58 in the control group. Median (IQR) IgG concentrations were lower in the study group (99 BAU/mL (40, 177)) than the control group (139 BAU/mL (120, 188)) following vaccination (p = 0.0032). Neutralizing antibodies were also lower in the study group compared with the control group (64% (23, 94) vs. 91% (85, 94), p < 0.001). The median IgA levels in the study group were also significantly lower when compared with the control group (6 U/mL (3, 34) vs. 13 U/mL (7, 30), p = 0.0097). In the study group, the percentages of patients who achieved positive IgG, neutralizing antibody and IgA levels were 81%, 75%, and 40%, respectively. In the control group, all participants (100%) had positive IgG and neutralizing antibody levels while 62% had positive IgA levels. CONCLUSION: In patients with IBD receiving infliximab combination therapy, SARS-CoV2 IgG, IgA, and neutralizing antibody levels after BNT162b2 vaccination were lower compared with healthy participants. However, most patients treated with infliximab combination therapy seroconverted after two doses of the vaccine.

9.
Microorganisms ; 9(11)2021 Nov 11.
Article in English | MEDLINE | ID: covidwho-1512502

ABSTRACT

Glucose-regulated protein 78 (GRP78) might be a receptor for SARS-CoV-2 to bind and enter the host cell. Recently reported mutations in the spike glycoprotein unique to the receptor-binding domain (RBD) of different variants might increase the binding and pathogenesis. However, it is still not known how these mutations affect the binding of RBD to GRP78. The current study provides a structural basis for the binding of GRP78 to the different variants, i.e., B.1.1.7, B.1.351, B.1.617, and P.1 (spike RBD), of SARS-CoV-2 using a biomolecular simulation approach. Docking results showed that the new variants bound stronger than the wild-type, which was further confirmed through the free energy calculation results. All-atom simulation confirmed structural stability, which was consistent with previous results by following the global stability trend. We concluded that the increased binding affinity of the B.1.1.7, B.1.351, and P.1 variants was due to a variation in the bonding network that helped the virus induce a higher infectivity and disease severity. Consequently, we reported that the aforementioned new variants use GRP78 as an alternate receptor to enhance their seriousness.

10.
Surg Obes Relat Dis ; 16(12): 1910-1918, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1454528

ABSTRACT

BACKGROUND: Bariatric surgery is well established as a treatment for obesity and associated complications. This procedure improves metabolic homeostasis through changes in energy expenditure. We hypothesized that sleeve gastrectomy (SG) improves metabolic homeostasis by modulating energy expenditure and enhancing thermogenesis through increasing the expression level of meteorin-like protein (METRNL) and fibronectin type III domain-containing protein 5 (FNDC5/Irisin) through uncoupling proteins 1/2/3 (UCP1, UCP2, and UCP3). OBJECTIVES: To study the effect of SG on the levels of proteins involved in thermogenesis process. SETTING: Laboratory rats at Kuwait University. METHODS: Male Sprague-Dawley rats, aged 4 to 5 weeks, were divided into 2 groups, control (n = 11) and diet-induced obesity (DIO) (n = 22). The control group was fed regular rat chow ad libitum, whereas the DIO group was fed cafeteria diet "high-fat/carbohydrate diet" ad libitum. At 21 weeks, rats in the DIO group that weighed 20% more than the control group animals underwent surgery. These rats were randomly subdivided into Sham and SG operation groups. Gene expression was evaluated, and enzyme-linked immunosorbent assays were employed to assess the changes in gene and protein levels in tissue and circulation. RESULTS: The protein expression data revealed an increase in METRNL levels in the muscles and white adipose tissue of SG animals. METRNL level in circulation in SG animals was reduced compared with control and Sham rats. The level of Irisin increased in the muscle of SG animals compared with the control and Sham group animals; however, a decrease in Irisin level was observed in the white adipose tissue and brown adipose tissue of SG animals compared with controls. Gene expression analysis revealed decreased METRNL levels in muscle tissues in the SG group compared with the control group animals. Increased expression of FNDC5 (Irisin), UCP2, and UCP3 in the muscle tissue of SG animals was also observed. Furthermore, the levels of UCP1, UCP2, UCP3, and METRNL in the brown adipose tissue of SG animals were upregulated. No significant alteration in the gene expression of Irisin was observed in brown adipose tissue. CONCLUSIONS: Sleeve gastrectomy induces weight loss through complex mechanisms that may include browning of fat.


Subject(s)
Adipose Tissue, Brown , Obesity , Adipose Tissue/metabolism , Animals , Diet , Fibronectins/genetics , Fibronectins/metabolism , Gastrectomy , Kuwait , Male , Mitochondrial Uncoupling Proteins , Muscles/metabolism , Obesity/genetics , Obesity/surgery , Rats , Rats, Sprague-Dawley
11.
Virus Res ; 303: 198522, 2021 10 02.
Article in English | MEDLINE | ID: covidwho-1447221

ABSTRACT

The B.1.1.7 SARS-CoV-2 strain that has emerged in the UK in early December presents seven mutations and three deletions on S-protein structure that could lead to a more infective strain. The P681H mutation in the "PRRAR" furin cleavage site might affect the binding affinity to furin enzyme and hence its infectivity. Therefore, in this study, various structural bioinformatics approaches were used to model the S-protein structure with the B.1.1.7 variant amino acid substitutions and deletions. In addition to modelling the binding of furin to the cleavage site of the wild-type and the B.1.1.7 variant. Conclusively the B.1.1.7 variant resulted in dynamic stability, conformational changes and variations in binding energies in the S-protein structure, resulting in a more favourable binding of furin enzyme to the SARS-CoV-2 S-protein.


Subject(s)
Furin/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Binding Sites , Furin/chemistry , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Protein Binding , Protein Conformation , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
12.
Hum Vaccin Immunother ; 17(11): 4121-4125, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1429135

ABSTRACT

Current vaccines, which induce a B-cell-mediated antibody response against the spike protein of SARS-CoV-2, have markedly reduced infection rates. However, the emergence of new variants as a result of SARS-CoV-2 evolution requires the development of novel vaccines that are T-cell-based and that target mutant-specific spike proteins along with ORF1ab or nucleocapsid protein. This approach is more accommodative in inducing highly neutralizing antibodies, without the risk of antibody-dependent enhancement, as well as memory CD8+T-cell immunity.


Subject(s)
Antibody-Dependent Enhancement , COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , Humans , RNA, Messenger , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccination
13.
Saudi J Biol Sci ; 28(11): 6645-6652, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1313431

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) was caused by the newly emerged corona virus (2019-nCoV alias SARS-CoV-2) that resembles the severe acute respiratory syndrome virus (SARS-CoV). SARS-CoV-2, which was first identified in Wuhan (China) has spread globally, resulting in a high mortality worldwide reaching ~4 million deaths to date. As of first week of July 2021, ~181 million cases of COVID-19 have been reported. SARS-CoV-2 infection is mediated by the binding of virus spike protein to Angiotensin Converting Enzyme 2 (ACE2). ACE2 is expressed on many human tissues; however, the major entry point is probably pneumocytes, which are responsible for synthesis of alveolar surfactant in lungs. Viral infection of pneumocytes impairs immune responses and leads to, apart from severe hypoxia resulting from gas exchange, diseases with serious complications. During viral infection, gene products (e.g. ACE2) that mediate viral entry, antigen presentation, and cellular immunity are of crucial importance. Human leukocyte antigens (HLA) I and II present antigens to the CD8+ and CD4+ T lymphocytes, which are crucial for immune defence against pathogens including viruses. HLA gene variants affect the recognition and presentation of viral antigenic peptides to T-cells, and cytokine secretion. Additionally, endoplasmic reticulum aminopeptidases (ERAP) trim antigenic precursor peptides to fit into the binding groove of MHC class I molecules. Polymorphisms in ERAP genes leading to aberrations in ERAP's can alter antigen presentation by HLA class I molecules resulting in aberrant T-cell responses, which may affect susceptibility to infection and/or activation of immune response. Polymorphisms from these genes are associated, in global genetic association studies, with various phenotype traits/disorders many of which are related to the pathogenesis and progression of COVID-19; polymorphisms from various genes are annotated in genotype-tissue expression data as regulating the expression of ACE2, HLA's and ERAP's. We review such polymorphisms and illustrate variations in their allele frequencies in global populations. These reported findings highlight the roles of genetic modulators (e.g. genotype changes in ACE2, HLA's and ERAP's leading to aberrations in the expressed gene products or genotype changes at other genes regulating the expression levels of these genes) in the pathogenesis of viral infection.

14.
Biomolecules ; 11(7)2021 06 22.
Article in English | MEDLINE | ID: covidwho-1282440

ABSTRACT

SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) protein is the target for the antiviral drug Remdesivir (RDV). With RDV clinical trials on COVID-19 patients showing a reduced hospitalisation time. During the spread of the virus, the RdRp has developed several mutations, with the most frequent being A97V and P323L. The current study sought to investigate whether A97V and P323L mutations influence the binding of RDV to the RdRp of SARS-CoV-2 compared to wild-type (WT). The interaction of RDV with WT-, A97V-, and P323L-RdRp were measured using molecular dynamic (MD) simulations, and the free binding energies were extracted. Results showed that RDV that bound to WT- and A97V-RdRp had a similar dynamic motion and internal residue fluctuations, whereas RDV interaction with P323L-RdRp exhibited a tighter molecular conformation, with a high internal motion near the active site. This was further corroborated with RDV showing a higher binding affinity to P323L-RdRp (-24.1 kcal/mol) in comparison to WT-RdRp (-17.3 kcal/mol). This study provides insight into the potential significance of administering RDV to patients carrying the SARS-CoV-2 P323L-RdRp mutation, which may have a more favourable chance of alleviating the SARS-CoV-2 illness in comparison to WT-RdRp carriers, thereby suggesting further scientific consensus for the usage of Remdesivir as clinical candidate against COVID-19.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase/genetics , Point Mutation , SARS-CoV-2/genetics , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Binding Sites/drug effects , COVID-19/virology , Catalytic Domain/drug effects , Humans , Molecular Dynamics Simulation , Point Mutation/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology
15.
Chembiochem ; 22(16): 2641-2649, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1279349

ABSTRACT

The evolution of new SARS-CoV-2 variants around the globe has made the COVID-19 pandemic more worrisome, further pressuring the health care system and immunity. Novel variations that are unique to the receptor-binding motif (RBM) of the receptor-binding domain (RBD) spike glycoprotein, i. e. L452R-E484Q, may play a different role in the B.1.617 (also known as G/452R.V3) variant's pathogenicity and better survival compared to the wild type. Therefore, a thorough analysis is needed to understand the impact of these mutations on binding with host receptor (RBD) and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to explore the impact of specific mutations (L452R-E484Q) in the B.1.617 variant on the binding of RBD to the host receptor ACE2. Our analysis revealed that the B.1.617 variant possesses different dynamic behaviours by altering dynamic-stability, residual flexibility and structural compactness. Moreover, the new variant had altered the bonding network and structural-dynamics properties significantly. MM/GBSA technique was used, which further established the binding differences between the wild type and B.1.617 variant. In conclusion, this study provides a strong impetus to develop novel drugs against the new SARS-CoV-2 variants.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Protein Domains , Virulence
16.
Biomolecules ; 11(4)2021 04 14.
Article in English | MEDLINE | ID: covidwho-1186889

ABSTRACT

The SARS-CoV-2 non-structural protein (nsp) nsp10-nsp16 complex is essential for the 2'-O-methylation of viral mRNA, a crucial step for evading the innate immune system, and it is an essential process in SARS-CoV-2 life cycle. Therefore, detecting molecules that can disrupt the nsp10-nsp16 interaction are prospective antiviral drugs. In this study, we screened the North African Natural Products database (NANPDB) for molecules that can interact with the nsp10 interface and disturb the nsp10-nsp16 complex formation. Following rigorous screening and validation steps, in addition to toxic side effects, drug interactions and a risk /benefit assessment, we identified four compounds (genkwanin-6-C-beta-glucopyranoside, paraliane diterpene, 4,5-di-p-trans-coumaroylquinic acid and citrinamide A) that showed the best binding affinity and most favourable interaction with nsp10 interface residues. To understand the conformational stability and dynamic features of nsp10 bound to the four selected compounds, we subjected each complex to 200 ns molecular dynamics simulations. We then calculated the free binding energies of compounds interacting with nsp10 structure using the molecular mechanics-generalised Born surface area (MMGBSA). Of the four compounds, genkwanin-6-C-beta-glucopyranoside demonstrated the most stable complex with nsp10, in addition to a tighter binding affinity of -37.4 ± 1.3 Kcal/mol. This potential to disrupt the nsp10-nsp16 interface interaction and inhibit it now sets the path for functional studies.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/metabolism , Viral Regulatory and Accessory Proteins/metabolism , Antiviral Agents/chemistry , Biological Products/chemistry , Drug Discovery , Humans , Methyltransferases , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Interaction Maps/drug effects , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Regulatory and Accessory Proteins/antagonists & inhibitors
17.
Heliyon ; 7(4): e06706, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1163824

ABSTRACT

BACKGROUND: COVID-19 has a highly variable clinical presentation, ranging from asymptomatic to severe respiratory symptoms and death. Diabetes seems to be one of the main comorbidities contributing to a worse COVID-19 outcome. OBJECTIVE: In here we analyze the clinical characteristics and outcomes of diabetic COVID-19 patients Kuwait. METHODS: In this single-center, retrospective study of 417 consecutive COVID-19 patients, we analyze and compare disease severity, outcome, associated complications, and clinical laboratory findings between diabetic and non-diabetic COVID-19 patients. RESULTS: COVID-19 patients with diabetes had more ICU admission than non-diabetic COVID-19 patients (20.1% vs. 16.8%, p < 0.001). Diabetic COVID-19 patients also recorded higher mortality in comparison to non-diabetic COVID-19 patients (16.7% vs. 12.1%, p < 0.001). Diabetic COVID-19 patients had significantly higher prevalence of comorbidities, such as hypertension. Laboratory investigations also highlighted notably higher levels of C-reactive protein in diabetic COVID019 patients and lower estimated glomerular filtration rate. They also showed a higher incidence of complications. logistic regression analysis showed that every 1 mmol/L increase in fasting blood glucose in COVID-19 patients is associated with 1.52 (95% CI: 1.34-1.72, p < 0.001) times the odds of dying from COVID-19. CONCLUSION: Diabetes is a major contributor to worsening outcomes in COVID-19 patients. Understanding the pathophysiology underlining these findings could provide insight into better management and improved outcome of such cases.

18.
Heliyon ; 7(2): e06133, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1051652

ABSTRACT

The severity of the new COVID-19 pandemic caused by the SARS-CoV-2 virus is strikingly variable in different global populations. SARS-CoV-2 uses ACE2 as a cell receptor, TMPRSS2 protease, and FURIN peptidase to invade human cells. Here, we investigated 1,378 whole-exome sequences of individuals from the Middle Eastern populations (Kuwait, Qatar, and Iran) to explore natural variations in the ACE2, TMPRSS2, and FURIN genes. We identified two activating variants (K26R and N720D) in the ACE2 gene that are more common in Europeans than in the Middle Eastern, East Asian, and African populations. We postulate that K26R can activate ACE2 and facilitate binding to S-protein RBD while N720D enhances TMPRSS2 cutting and, ultimately, viral entry. We also detected deleterious variants in FURIN that are frequent in the Middle Eastern but not in the European populations. This study highlights specific genetic variations in the ACE2 and FURIN genes that may explain SARS-CoV-2 clinical disparity. We showed structural evidence of the functionality of these activating variants that increase the SARS-CoV-2 aggressiveness. Finally, our data illustrate a significant correlation between ACE2 variants identified in people from Middle Eastern origins that can be further explored to explain the variation in COVID-19 infection and mortality rates globally.

19.
Int J Infect Dis ; 103: 611-616, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1039365

ABSTRACT

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has caused an exponential rise in death rates and hospitalizations. The aim of this study was to characterize the D614G substitution in the severe acute respiratory syndome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S protein), which may affect viral infectivity. METHODS: The effect of D614G substitution on the structure and thermodynamic stability of the S protein was analyzed with use of DynaMut and SCooP. HDOCK and PRODIGY were used to model furin protease binding to the S protein RRAR cleavage site and calculate binding affinities. Molecular dynamics simulations were used to predict the S protein apo structure, the S protein-furin complex structure, and the free binding energy of the complex. RESULTS: The D614G substitution in the G clade of SARS-CoV-2 strains introduced structural mobility and decreased the thermal stability of the S protein (ΔΔG = -0.086 kcal mol-1). The substitution resulted in stronger binding affinity (Kd = 1.6 × 10-8) for furin, which may enhance S protein cleavage. The results were corroborated by molecular dynamics simulations demonstrating higher binding energy of furin and the S protein D614G mutant (-61.9 kcal mol-1 compared with -56.78 kcal mol-1 for wild-type S protein). CONCLUSIONS: The D614G substitution in the G clade induced flexibility of the S protein, resulting in increased furin binding, which may enhance S protein cleavage and infiltration of host cells. Therefore, the SARS-CoV-2 D614G substitution may result in a more virulent strain.


Subject(s)
COVID-19/etiology , Furin/metabolism , Mutant Proteins/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Humans , Protein Binding , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Thermodynamics
20.
Front Pharmacol ; 11: 587451, 2020.
Article in English | MEDLINE | ID: covidwho-1000124

ABSTRACT

COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus-2, which has infected over thirty eight million individuals worldwide. Emerging evidence indicates that COVID-19 patients are at a high risk of developing coagulopathy and thrombosis, conditions that elevate levels of D-dimer. It is believed that homocysteine, an amino acid that plays a crucial role in coagulation, may also contribute to these conditions. At present, multiple genes are implicated in the development of these disorders. For example, single-nucleotide polymorphisms (SNPs) in FGG, FGA, and F5 mediate increases in D-dimer and SNPs in ABO, CBS, CPS1 and MTHFR mediate differences in homocysteine levels, and SNPs in TDAG8 associate with Heparin-induced Thrombocytopenia. In this study, we aimed to uncover the genetic basis of the above conditions by examining genome-wide associations and tissue-specific gene expression to build a molecular network. Based on gene ontology, we annotated various SNPs with five ancestral terms: pulmonary embolism, venous thromboembolism, vascular diseases, cerebrovascular disorders, and stroke. The gene-gene interaction network revealed three clusters that each contained hallmark genes for D-dimer/fibrinogen levels, homocysteine levels, and arterial/venous thromboembolism with F2 and F5 acting as connecting nodes. We propose that genotyping COVID-19 patients for SNPs examined in this study will help identify those at greatest risk of complications linked to thrombosis.

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